Process for producing 2-aminobenzophenone compound

ABSTRACT

A 2-aminobenzophenone represented by formula (2) is obtained by heating an arylsulfonamide represented by formula (1) in the presence of aluminum chloride.

TECHNICAL FIELD

The present invention relates to a process for producing2-aminobenzophenones which can be useful intermediates of cholesterolreducing agents (HMG-CoA reductase inhibitors), mental disorders agentsand anti-inflammatory agents.

BACKGROUND ART

The quinoline compound represented by formula (3) is disclosed inJP-A-1-279866, EP-A-304063 and U.S. Pat. No. 5,011,930 as a usefulcholesterol reducing agent (HMG-CoA reductase inhibitor), and the2-aminobenzophenone represented by formula (2) (wherein X=4-F) isreported to be useful as its intermediate in Tetrahedron Letters, 1993,vol. 34, p.8267.

Likewise, the mental disorder agent represented by formula (4) and theanti-inflammatory agent represented by formula (5) are also synthesizedvia 2-aminobenzophenones. Therefore, establishment of an industriallyadvantageous process for their production is of great significance.

Some processes have been reported for production of 2-aminobenzophenones[review: Synthesis, 677 (1980)]. The process using anthranilic acid asthe starting material which comprises formation of an acid chlorideafter protection of the amino group by a tosyl group and theFriedel-Crafts reaction followed by deprotection has been known long(Org. Synth. Coll. Vol. IV, 34 (1963), Scheme 1) and appreciated for thelow raw material cost and the reliability. However, because of the useof concentrated sulfuric acid as the solvent essential for the lastdetosylation step, the process admittedly has a serious problem withwaste liquor disposal from the industrial aspect. Conversely, this meansthat the production route is pretty fine only if this problem is solved.

wherein X is a hydrogen atom, a C₁₋₄ alkyl group or a halogen atom.

DISCLOSURE OF THE INVENTION

As a result of their extensive research to solve the above-mentionedproblem, the present inventors found that heating in the presence of anexcess of aluminum chloride subsequent to the Friedel-Crafts reactionfacilitates detosylation as shown in Scheme 2 and have accomplished thepresent invention on the basis of the discovery. The process of thepresent invention also improves the total yield, for example to 64%,based on anthranilic acid having a tosyl-protected amino group, in thecase of the compound (2) (X=4-F) which is an intermediate of thecholesterol reducing agent (HMG-CoA reductase inhibitor)represented byformula (3). A cutback in materials and a great improvement inproduction efficiency can be accomplished by conducting the three stepsstarting from the formation of the acid chloride in the same solventcontinuously.

Namely, the present invention relates to a process for producing a2-aminobenzophenone represented by formula (2) characterized by heatingan arylsulfonamide represented by formula (1) in the presence ofaluminum chloride.

The process of the present invention dispenses with the conventionalneed for concentrated sulfuric acid in detosylation and is advantageousin respect of waste liquor disposal. The process of the presentinvention also makes it possible to conduct the Friedel-Crafts reactionand detosylation without a break and contributes to a cutback inmaterial and a great improvement in production efficiency in productionof a medical intermediate represented by formula (2).

BEST MODE FOR CARRYING OUT THE INVENTION

Now, the process of the present invention will be described.

As the reaction solvent used in the formation of the chloride oftosylanthranilic acid, although a halogenated aliphatic hydrocarbon suchas dischloroethane could be used as disclosed in Org. Synth. Coll. Vol.IV mentioned above, it is advantageous in terms of efficiency to use ahigh-boiling substituted aromatic hydrocarbon (having a halogen atom ora nitro group as the substituent) such as ortho-dichlorobenzene so thatthe resulting phosphorus oxychloride can be distilled off at reducedpressure, leaving the solvent behind. The subsequent Friedel-Craftsreaction and detosylation reaction can be conducted directly in thesolution of the acid chloride in the substituted aromatic hydrocarbon.

The formation of the acid chloride can be carried out at temperatures offrom 0 to 100° C., but it is preferred to add phosphorus pentachlorideat from 15 to 30° C. and then complete the reaction at elevatedtemperatures of from 70 to 90° C. The sequential Friedel-Crafts reactionand detosylation reaction are preferred to be carried out by addingaluminum chloride at from 15 to 30° C., continuing the reactions at from40 to 60° C. and completing the reaction at elevated temperatures offrom 70 to 90° C. Although from 1.1 to 1.2 times as many moles ofaluminum chloride is sufficient for the Friedel-Crafts reaction, it ispreferred to use from 2 to 4 times as many moles of aluminum chloride inorder to proceed to the detosylation without a break. An excess ofaluminum chloride, though not being influential in the reactions, wouldadd to the burden of post-treatment. Conversely, shortage of aluminumchloride would be an obstacle to completion of the reactions.

In the meantime, it is advantageous in terms of efficiency to isolateand purify the 2-aminobenzophenone in the form of the methanesulfonatesalt in case that contamination with the following by-product occurs.

Now, the present invention will be described in further details withreference to Examples. However, the present invention is by no meansrestricted to these specific Examples.

REFERENCE EXAMPLE 1 Preparation of Tosylanthranilic Acid

In a 1 L reaction flask equipped with a condenser, 34.25 g (0.25 mol) ofanthranilic acid, 411 g of water and 63.59 g (0.6 mol) of sodiumcarbonate were heated. The resulting reaction solution was maintained atan inner temperature of 78° C. for 30 minutes and then cooled to 67° C.,and 57.2 g (0.3 mol) of tosyl chloride was added in two portions. Thereaction solution gradually generated heat upon addition of tosylchloride and turned homogeneous at 78° C. The reaction solution was agedat 80° C. for 1 hour. Crystals started to separate out in the first tenor so minutes of the aging. The completion of the reaction was confirmedby liquid chromatography, and the reaction solution was carefullyneutralized with concentrated hydrochloric acid and allowed to cool. Thecrystals were collected by filtration at room temperature and washedwith 100 ml of dilute hydrochloric acid at pH 3 and with 125 ml ofwater. Recrystallization from 247 g of n-propanol afforded 56.97 g oftosylanthranilic acid in a 78.3% yield.

Example 1 Preparation of 2-amino-4′-fluorobenzophenone

In a 1 L reaction flask equipped with a condenser, 56.97 g (0.196 mol)of tosylanthranilic acid was suspended in 372.0 g of o-dichlorobenzene(hereinafter referred to as DCB), and 42.81 g (0.206 mol) of phosphoruspentaoxychloride was added all at once. The reaction solution wasstirred at room temperature for about 1.5 hours, generating noticeableslight heat. Then, the reaction solution was heated and maintained at aninner temperature of 85° C. for 1 hour. The reaction solution turnedhomogenous upon heating immediately, and generation of hydrogen chloridegas was observed as the reaction proceeded. The reaction solution wasaged at an inner temperature of 85° C. for 1 hour and then allowed tocool, and the resulting phosphorus oxychloride and the DCB weredistilled off under reduced pressure in a total amount of 90 g. Thereminder was allowed to cool to room temperature, and 78.5 g of aluminumchloride and 47 g of fluorobenzene were added. Sight heat generation wasrecognized, and a homogeneous solution was formed when the aluminumchloride melted at 50° C. The reaction solution was heated to an innertemperature of 80° C. and maintained at the same temperature for 3hours. The completion of the reaction was confirmed by liquidchromatography, and the reaction solution was allowed to cool and pouredinto 700 g of ice-cold water carefully so that the liquid temperaturewould not exceed 30° C. The solution was heated to an inner temperatureof from 70 to 80° C. to homogeneity and allowed to separate while it washot. The aqueous layer was extracted with 150 g of DCB at 70° C. again,and the organic layers was combined and washed with 250 g of water.After 250 g of DCB was distilled off under reduced pressure, the organiclayer was allowed to cool. It was recognized that crystals started toseparated out at about 40° C. Aging of the crystals at from 0 to 5° C.for 3 hours followed by filtration, washing with 25 g of cold DCB anddrying at 60° C. under reduced pressure afforded 26.9 g of the desiredproduct in a 63.8% yield. m.p. 129-130° C.

What is claimed is:
 1. A process for producing a 2-aminobenzophenonerepresented by formula (2) comprising: heating an arylsulfonamiderepresented by formula (1) in the presence of aluminum chloride:

wherein X is a hydrogen atom, a C₁₋₄ alkyl group or a halogen atom.